IllnessHypogonadotropic hypogonadism, Kallmann syndrome; differential diagnosis

NGS +

[Sanger]

Kallmann syndrome (KS) is a rare genetic disorder defined by delayed or absent puberty with impaired/absent sense of smell. Closely related is normosomal-idiopathic hypogonadotropic hypogonadism (nIHH). Both diseases lack the gonadotropin-releasing hormone. KS and nIHH occur in both sexes, men are diagnosed more frequently. Patients with KS/nIHH are typically noticed in adolescence due to delayed puberty. While reproductive symptoms predominate, facial abnormalities (cleft lip/palate), lack of a kidney, shortened fingers, numbness, bone and tooth defects and disturbed eye movements are also observed. All monogenic inheritance patterns are observed, the penetrance for the KS phenotype is virtually complete for some genes such as ANOS1 with respect to the core symptoms and high for recessively inherited forms. Comprehensive gene panel diagnostics reveal pathogenic sequence changes in up to 60% of affected individuals, a normal DNA result does not exclude clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1334/

• *PROK/-R2 inheritance: https://eje.bioscientifica.com/downloadpdf/journals/eje/178/3/EJE-17-0749.pdf
• Adrenal hypoplasia, congenital (NR0B1)
• Allelic: 46XY sex reversal 2, dosage-sensitive (NR0B1)
• Allelic: Blood group, John-Milton-Hagen system (SEMA7A)
• Allelic: CHARGE syndrome (CHD7)
• Allelic: Encephalocraniocutaneous lipomatosis; Hartsfield syndrome; Jackson-Weiss syndrome (FGFR1)
• Allelic: Luteinizing hormone resistance, female (LHCGR)
• Allelic: Osteoglophonic dysplasia; Pfeiffer syndrome; Trigonocephaly 1 (FGFR1)
• Allelic: Precocious puberty, central, 1 (KISS1R)
• Allelic: Precocious puberty, male (LHCGR)
• CHARGE syndrome (SEMA3E)
• Congenital hypogonadotropic hypogonadism [panelapp] (KLB)
• Culler-Jones syndrome (GLI2)
• Dworschak-Punetha neurodevelopmental syndrome (PLXNA1)
• Growth hormone deficiency with pituitary anomalies (HESX1)
• Holoprosencephaly 9 (GLI2)
• Hypogonadotropic hypogonadism 1 with/-out anosmia; Kallmann syndrome 1 (ANOS1)
• Hypogonadotropic hypogonadism 10 with/-out anosmia (TAC3)
• Hypogonadotropic hypogonadism 11 with/-out anosmia (TACR3)
• Hypogonadotropic hypogonadism 12 with/without anosmia (GNRH1)
• Hypogonadotropic hypogonadism 13 with or without anosmia (KISS1)
• Hypogonadotropic hypogonadism 14 with/-out anosmia (WDR11)
• Hypogonadotropic hypogonadism 15 with/-out anosmia (HS6ST1)
• Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
• Hypogonadotropic hypogonadism 17 with/-out anosmia (SPRY4)
• Hypogonadotropic hypogonadism 18 with/-out anosmia (IL17RD)
• Hypogonadotropic hypogonadism 19 with/-out anosmia (DUSP6)
• Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Hypogonadotropic hypogonadism 20 with/-out anosmia (FGF17)
• Hypogonadotropic hypogonadism 21 with anosmia (FLRT3)
• Hypogonadotropic hypogonadism 22, with/-out anosmia (FEZF1)
• Hypogonadotropic hypogonadism 23 with/-out anosmia (LHB)
• Hypogonadotropic hypogonadism 24 without anosmia (FSHB)
• Hypogonadotropic hypogonadism 3 with/without anosmia (PROKR2)*
• Hypogonadotropic hypogonadism 4 with/without anosmia (PROK2)*
• Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
• Hypogonadotropic hypogonadism 6 with/without anosmia (FGF8)
• Hypogonadotropic hypogonadism 7 without anosmia (GNRHR)
• Hypogonadotropic hypogonadism 8 with/-out anosmia (KISS1R)
• Hypogonadotropic hypogonadism 9 with/-out anosmia (NSMF)
• Hypogonadotropic hypogonadism without anosmia; normosmic IHH [panelapp] (CCDC141)
• Leukodystrophy, hypomyelinating, 8, +/- oligodontia and/or hypogonadotropic hypogonadism (POLR3B)
• Leydig cell hypoplasia with hypergonadotropic hypogonadism (LHCGR)
• Leydig cell hypoplasia with pseudohermaphroditism (LHHCGR)
• Mental retardation, XL, syndromic 15, Cabezas type (CUL4B)
• Normosmic idiopathic hypogionadotrophic Hypogonadism [panelapp] (CCDC141)
• PCWH syndrome (SOX10)
• Perrault syndrome 3 (CLPP)
• Pituitary hormone deficiency, combined, 2 (PROP1)
• Pituitary hormone deficiency, combined, 3 (LHX3)
• Pituitary hormone deficiency, combined, 4 (LHX4)
• Pituitary hormone deficiency, combined, 5 (HESX1)
• Septooptic dysplasia (HESX1)
• Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
• Waardenburg syndrome, type 4C (SOX10)
• Woodhouse-Sakati syndrome (DCAF17)